Elucidation of NF2's tumor supressive function

阐明NF2的肿瘤抑制功能

• 批准号: 7474691
• 负责人: Chunling Yi
• 金额: $ 5.04万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474691
• 关键词: Animal Model; Binding; Data; Development; ERM protein; GTP Binding; Genes; Inborn Genetic Diseases; Lead; Malignant Neoplasms; Modality; Names; Neurofibromatosis 2; Neurofibromin 2; Phenotype; Phosphotransferases; Proteins; Schwann Cells; Signal Transduction; Testing; Therapeutic; Tumor Suppressor Proteins; VIII cranial nerve Tumor; Validation; ezrin; gene function; moesin; p21 activated kinase; radixin protein; research study; stem; tumor

DESCRIPTION (provided by applicant): Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by development of Schwann cell tumors of the eighth cranial nerve. The NF2 gene encodes a protein named merlin, which is highly related to the ERM proteins (moesin, ezrin and radixin). Merlin is phosphorylated by Paks, which bind to activated (GTP-bound) Rac/Cdc42 and function as their direct effectors. Recent data implicate that merlin negatively regulates Rac/cdc42 signaling by directly interacting with and inhibiting Paks. The proposed project is geared towards establishing whether the Pak-inhibitory function of merlin is also merlin's tumor suppressive function. Furthermore, cellular and animal models will be employed to test whether inhibiting Pak function can reverse the transformed and cancer phenotypes that arise from NF2 deficiency. Finally, experiments will be carried out to identify additional mechanisms that may contribute to NF2 tumor suppressor function. Taken together, these studies will lead to a better understanding of merlin's tumor suppressive function. The validation of Paks as potential targets for inhibition, stemming from these studies, will point directly at approaches for the development of therapeutics towards the treatment of neurofibromatosis type 2.

描述（由申请人提供）：2型神经纤维瘤病（NF 2）是一种遗传性疾病，其特征为第八脑神经的许旺细胞瘤的发展。NF 2基因编码一种名为merlin的蛋白，该蛋白与ERM蛋白（膜突蛋白、埃兹蛋白和根蛋白）高度相关。Merlin被Paks磷酸化，Paks与激活的（GTP结合的）Rac/Cdc 42结合，并作为其直接效应物发挥作用。最近的数据表明，梅林负调控Rac/cdc 42信号直接相互作用和抑制Paks。该项目旨在确定梅林的Pak抑制功能是否也是梅林的肿瘤抑制功能。此外，将采用细胞和动物模型来测试抑制Pak功能是否可以逆转由NF 2缺乏引起的转化和癌症表型。最后，将进行实验，以确定可能有助于NF 2肿瘤抑制功能的其他机制。总之，这些研究将使我们更好地了解梅林的肿瘤抑制功能。来自这些研究的Paks作为抑制的潜在靶点的验证将直接指向治疗2型神经纤维瘤病的治疗方法的开发。

项目成果

Development of small-molecule inhibitors of the group I p21-activated kinases, emerging therapeutic targets in cancer.

• DOI: 10.1016/j.bcp.2010.03.012
• 发表时间: 2010-09-01
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Yi, Chunling;Maksimoska, Jasna;Marmorstein, Ronen;Kissil, Joseph L.
• 通讯作者: Kissil, Joseph L.